About one-half of people with heart failure (HF) have heart failure with preserved ejection fraction (HFpEF) (1). There is no proven effective treatment that prolongs life for people with HFpEF. In addition to left ventricular (LV) diastolic dysfunction, afflicted patients display LV systolic dysfunction (2–6), chronotropic incompetence (5,7), abnormal vasorelaxation (5,7), deranged ventricular-arterial coupling (3,5), right heart dysfunction (8,9), impaired endothelium-dependent vasodilation (5), and abnormalities in the periphery (10,11). Given this complexity, HFpEF is often considered to represent a group of multiple diseases caused by different etiologies that produce the same symptoms. If true, then patients presenting with HFpEF should be “subphenotyped” into more mechanistically homogenous bins to optimize treatment (12).

However, there is also evidence that people with HFpEF display multiple impairments in cardiac, vascular, and peripheral function that coexist with one another, and that the totality of these impairments is what drives the clinical syndrome of HF (5,13). If that is the case, then systemic processes are likely to underlie these varied reserve impairments, and interventions targeting those processes might be of the greatest yield in treatment. This question fundamentally boils down to whether HFpEF patients ought to be taxonomically “lumped” or “split” as we ponder disease progression and new interventions targeting this progression.

In this issue of the Journal, Kosmala et al. (14) provide intriguing new data that take us another step closer to understanding how HFpEF should be conceptualized. The investigators performed a comprehensive echocardiographic assessment at rest and following maximal effort cardiopulmonary exercise testing in people with normal LV ejection fraction. They defined subjects with structural findings typical of HFpEF (diastolic dysfunction with LV hypertrophy and/or reduced LV global longitudinal strain [GLS]) but no symptoms or exercise limitation as stage B HFpEF (n = 60), and then compared this group to people with clinical HFpEF (stage C, defined by typical signs and symptoms, diastolic dysfunction, and peak aerobic capacity <80% of age- and sex-predicted values).

Compared with people at risk for HFpEF (stage B), subjects with symptomatic HFpEF (stage C) displayed greater structural remodeling (higher LV mass, left atrial dilation), more diastolic dysfunction (lower peak early diastolic mitral annular velocity [e′] velocities, higher estimated LV filling pressure by peak early diastolic mitral flow velocity [E]/e′ ratio), and impaired LV systolic function (lower GLS) (14). With exercise, these impairments became more dramatic in stage C compared with stage B, with less enhancement in e′, GLS, and ejection fraction; greater increase in E/e′; altered ventricular-arterial coupling; chronotropic incompetence, and impaired cardiac output reserve. Blunted increases in heart rate, GLS, and cardiac output each effectively separated stage B from stage C patients (C-statistics 0.75 to 0.78). These findings confirm and extend previous studies comparing subjects with HFpEF with age-matched control subjects, as well as patients with asymptomatic hypertensive heart disease (5,13). A second control population of patients with HFpEF risk factors but no cardiac structural remodeling (stage A) was not included, but a previous study from the same investigators convincingly showed that exercise capacity is more impaired in stage B than A HFpEF, despite the absence of HF symptoms in both (15).

To further explore the hypothesis that disease progression in HFpEF is tied to global reserve limitations, the investigators grouped the subjects with stage C HFpEF into 3 cohorts on the basis of echocardiography-estimated LV filling pressures (E/e′ ratio) at rest and following exercise (14). This subgrouping is supported by previous studies showing that despite normal values at rest, patients with early-stage HFpEF display elevation in filling pressures only during exercise (16). Patients with normal E/e′ (<13) at rest and following exercise were termed group C1 (n = 63); those with normal E/e′ at rest, but high E/e′ following exercise were C2 (n = 118); and those with elevated E/e’ at both stages were C3. Exercise capacity (peak oxygen consumption) decreased from C1 to C2 and C3, in tandem with worsening left atrial and right ventricular function at rest, greater chronotropic incompetence, and blunted diastolic and impaired contractile reserves during exercise. These data, together with the current body of published data, strongly support the hypothesis that progressive acquisition of worsening diastolic, systolic, vascular, and chronotropic reserve limitations underlies the progression from patients at risk to patients with progressively more symptomatic HFpEF (5,7,14). In other words, functional limitation in HFpEF does not appear to be caused by 1 discrete mechanism that varies from person to person, but from the confluence of multiple cardiovascular reserve limitations that limit the body’s ability to cope with the physiological demands of exercise (5).

Although these findings are more supportive of “lumping,” they do not exclude a potentially important role for “splitting,” because it is likely that some mechanisms play a more dominant role in some patients with HFpEF than in others (12). However, the current data do support the hypothesis that overarching, systemic processes drive global reserve limitations in HFpEF because, as disease severity progresses from stage B through stage C, more limitations coexist and the severity of those limitations worsens (14).

The next question becomes what might these systemic processes be? Multiple lines of evidence suggest that impairments in nitric oxide (NO) availability play a central, unifying role in the pathophysiology of HFpEF (17), and clinical trials targeting this pathway are underway. Inorganic nitrite has recently emerged as a very promising agent in this regard (18). Reduction of nitrite to NO in the vasculature is enhanced during venous hypoxia, as in during exercise, and because reserve limitations in HFpEF are most profound during exertion (3–5,14,16), this may allow more targeted NO delivery at the time of greatest need. Indeed, we recently showed, in a placebo-controlled trial, that acute administration of nitrite in subjects with HFpEF preferentially reduces LV filling pressures and improves cardiac reserve during exercise much more than rest (18). Other candidate systemic processes may contribute to global reserve limitations in HFpEF, including cardiovascular senescence, mitochondrial dysfunction, vascular rarefaction, and oxidative stress (19). Identifying these processes and methods of screening for them (e.g., biomarkers) represents an important area for future research.

Patients with atrial fibrillation, morbid obesity (body mass index >36 kg/m2), and coronary disease were excluded from the current study (14). Between 40% and 65% of patients with HFpEF display these comorbidities, so this is an important limitation to consider. Ventricular and vascular assessments were performed following, but not during, exercise, which may have reduced the sensitivity to detect limitations because hemodynamics may rapidly return to baseline following cessation of activity (16). Recent studies identified peripheral limitations to exercise as having an important role in some HFpEF patients, but this was not assessed in the current study (10,11).

In summary, the data from Kosmala et al. (14) convincingly support the hypothesis that, although there is mechanistic heterogeneity in HFpEF, it is the complex amalgamation of multiple cardiac and vascular impairments that causes symptoms and aerobic limitation (14). HFpEF patients with the most severe exercise intolerance display the most prevalent and severe reserve limitations, whereas patients with structural-functional changes, but no symptoms, display the fewest. It follows that interventions that mitigate loss of cardiac, vascular, and peripheral reserve may prevent disease progression in HFpEF, and that efforts to restore reserve may improve symptoms and exercise capacity. Although the question of lumping or splitting is far from resolved, it is safe to conclude from these (14) and other data (5,13) that HFpEF patients are more similar than different, and it seems likely that global reserve limitations in the heart, arteries, and periphery are tied to common systemic processes. Now it is time to identify what these processes are to then determine how to treat them.

Footnotes

↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.

Dr. Borlaug has reported that he has no relationships relevant to the contents of this paper to disclose.

(2009) Heart failure with preserved ejection fraction is characterized by dynamic impairment of active relaxation and contraction of the left ventricle on exercise and associated with myocardial energy deficiency. J Am Coll Cardiol54:402–409.

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